Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7]C)=[O:5].[CH3:14][O-:15].[Na+]>C(Cl)Cl>[Cl:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:15][CH3:14])[N:12]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)nc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.8 %

Procedure:
1.00 g of ethyl 2,6-dichloronicotinate was dissolved in 10 mL of methylene chloride, and 1.05 g of sodium methoxide (28 wt % of methanol solution) was added thereto at room temperature. After stirring at room temperature for 2 days, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 511 mg of methyl 6-chloro-2-methoxynicotinate as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1)(=O)[CH3:2].C(Cl)Cl.[Br:16]Br.[C:18]([NH:21][C:22]([NH2:24])=[S:23])(=[NH:20])[NH2:19]>CCOCC>[BrH:16].[C:11]([CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]2[N:24]=[C:22]([NH:21][C:18]([NH2:20])=[NH:19])[S:23][CH:2]=2)=[CH:5][CH:6]=1)#[N:12]
Reactant: BrBr
Reactant: CC(=O)c1ccc(CC#N)cc1
Reactant: N=C(N)NC(N)=S
Solvent: ClCCl
Solvent: CCOCC
Product: Br
Product: N#CCc1ccc(-c2csc(NC(=N)N)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6.36 g. (0.04 mole) of p-acetylphenyl acetonitrile in 100 ml. of methylene chloride is added 6.40 g. (0.04 mole) of bromine in 50 ml. of methylene chloride. The reaction solution is warmed for a few minutes and the heat then removed. After a few minutes the bromine color disappears. The reaction mixture is stirred an additional 1/2 hour at room temperature. The methylene chloride is removed in vacuo on a rotary evaporator. To the residue is added 100 ml. of ethanol and 4.73 g. (0.04 mole) of amidinothiourea. The reaction mixture is heated with stirring for 1 hour under reflux, cooled in ice and then filtered. There is obtained 7.6 g. of product, m.p. 242°-246° (dec.). Recrystallization is from ethanol to which is then added enough water to form a solution. Ether is added to the cloudy point. There is obtained 5.9 g. of crystals, m.p. 259°-261° (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C>C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([NH:1][C:32](=[O:34])[CH3:33])=[C:3]([C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])[O:4][C:5]3=[N:6][C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:12][CH:13]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1c(C(=O)C(C)(C)C)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.050 g (0.106 mmol) of the product from Example 17 in CH2Cl2 (1 mL) at 0° C. was treated with acetyl chloride (8 μL; 0.106 mmol) followed by triethylamine (15 μL; 0.106 mmol). After the addition, the reaction mixture was warmed to RT and stirred for 1 hour. The reaction was quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate-hexane gradient) gave the title compound. HPLC/MS: 515.0 (M+1), 517.0 (M+3); Rt=4.94 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1([O:33][C:34]([NH:36][OH:37])=O)C=CC=CC=1>C1COCC1>[OH:37][NH:36][C:34]([N:24]1[CH2:23][CH2:22][CH:21]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)[CH2:26][CH2:25]1)=[O:33]
Reactant: Cc1cnc(CN(C2CCNCC2)C2CCCc3cccnc32)c(C)c1
Reactant: O=C(NO)Oc1ccccc1
Solvent: C1CCOC1
Product: Cc1cnc(CN(C2CCN(C(=O)NO)CC2)C2CCCc3cccnc32)c(C)c1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 33.7 %

Procedure:
To a solution of (3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (150.0 mg, 0.428 mmol) in THF (5 mL) was added hydroxylamine carboxylic acid phenyl ester (75 mg, 0.449 mmol) and stirred for 17.5 h at reflux. The mixture was cooled to ambient temperature and concentrated in vacuo. Purification by flash chromatography on silica gel using CH2Cl2/MeOH/NH4OH (89:10:1) followed by purification by radial chromatography using CH2Cl2/MeOH/NH4OH (94:5:1) afforded COMPOUND 369 (59 mg, 34%) as white solid. 1H NMR (CDCl3) δ1.54-1.72 (m, 3H), 1.81-2.05 (m, 5H), 2.23 (s, 3H), 2.37 (s, 3H), 2.53-2.79 (m, 5H), 3.85-4.07 (m, 5H), 6.95-7.00 (m, 2H), 7.14 (s, 1H), 7.25 (d, 1H, J=4.2 Hz), 8.10 (s, 1H), 8.40 (d, 1H, J=3.7 Hz); 13C NMR (CDCl3) δ 17.90, 18.58, 21.71, 29.04, 29.37, 30.08, 31.25, 43.84, 53.30, 57.64, 60.19, 121.29, 131.51, 133.03, 134.11, 136.25, 138.92, 145.97, 146.88, 158.41, 160.63; ES-MS m/z 410 (M+H). Anal Calcd. For C23H31N5O2.0.1(H2O).0.3CH2Cl2): C, 64.07; H, 7.34; N, 16.03. Found: C, 64.13; H, 7.44; N, 15.69.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]([NH2:26])=[S:25])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].Br[CH2:34][C:35](=O)[CH3:36].C([O-])(=O)C.[Na+].O>C(O)C>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][CH:34]=[C:35]([CH3:36])[N:26]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CBr
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(N)=S)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)cs3)cc12
Yield: 72 %

Procedure:
A suspension of tert-butyl[6-(aminothiocarbonyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.46 g, 1 mmol), bromoacetone (0.20 g, 1.5 mmol) and sodium acetate (0.12 g, 1.5 mmol) in ethanol (10 ml) was refluxed under heating for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.36 g, 73.5%) as an amorphous.
Reaction SMILES: C([O:8][C:9]1[CH:39]=[CH:38][C:12]([C:13]([NH:15][C:16]2[CH:17]=[C:18]([C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[C:24]([NH:36][CH3:37])[N:23]=3)[CH:19]=[CH:20][CH:21]=2)=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(OCC)(=O)C.[H][H]>[C].[Pd].O1CCCC1>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[C:24]([NH:36][CH3:37])[N:23]=[C:22]2[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:39][CH:38]=2)[CH:17]=1
Reactant: [H][H]
Reactant: CNc1nc(-c2cccc(NC(=O)c3ccc(OCc4ccccc4)cc3)c2)c2cc(OC)c(OC)cc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1nc(-c2cccc(NC(=O)c3ccc(O)cc3)c2)c2cc(OC)c(OC)cc2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.7 %

Procedure:
388 mg of 4-[3-(4-benzyloxybenzoylamino)phenyl]-6,7-dimethoxy-2-methylaminoquinazoline obtained in Example 20 and 200 mg of 10% palladium-carbon powder (hydrate) were suspended in a mixed solvent of 10 ml ethyl acetate and 10 ml tetrahydrofuran. After the atmosphere was replaced with hydrogen, the mixture was stirred for 3 days at ordinary pressure at room temperature. The reaction solution was filtered, and the filtrate was evaporated. Then, the crude product was recrystallized from hexane-ethyl acetate to give 278 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O-:12])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH2:15](Br)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:17]([O:11][C:10](=[O:12])[CH:9]([P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:22])([CH3:18])[CH3:16]
Reactant: CCOP(=O)(CC(=O)[O-])OCC
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(CCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Diethylphosphonoacetate (1.00 g, 3.96 mmol) was added drop wise at 0° C. to a stirring suspension of sodium hydride (0.095 g, 3.96 mmol) in anhydrous THF (50 mL). The mixture was then allowed to stir for 10 minutes at 0° C. and then for 1 hour at room temperature before it was cooled again to 0° C. followed by the addition of phenethyl bromide (0.73 g, 3.96 mmol). The mixture was then allowed to proceed for 24 hours at room temperature. The solvent was evaporated and the residue was taken-up in water and extracted 4 times with ethyl acetate. The organic extracts were combined, washed with water and brine, dried using magnesium sulfate, filtered and evaporated. The crude residue was purified by flash chromatography (ethyl acetate in hexanes, 10%-50%) to afford the desired compound as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.18 (m, 2H), 7.09 (m, 2H), 4.07-3.99 (m, 4H), 2.82-2.72 (m, 1H), 2.69-2.60 (m, 1H), 2.54-2.45 (m, 1H), 2.25-2.12 (m, 1H), 2.08-1.94 (m, 1H), 1.41 (s, 9H), 1.24-1.18 (m, 6H); 13C (CDCl3, 400 MHz) δ 167.7, 140.4, 128.3, 128.2, 125.9, 81.5, 62.2, 46.3, 45.0, 34.1, 28.5, 27.7, 16.1; 31P (CDCl3, 400 MHz) δ 23.7. HRMS calcd. for C18H29O5P 356.1753, found 356.1757.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CC(OC([N:28](C(OC(C)(C)C)=O)[C:29]1[NH:30][C:31]([C:35](O)=[O:36])=[C:32]([Cl:34])[N:33]=1)=O)(C)C.ClC1N=C(NC(OC(C)(C)C)=O)NC=1C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:95]([OH:101])([C:97]([F:100])([F:99])[F:98])=[O:96]>CN(C=O)C>[F:98][C:97]([F:100])([F:99])[C:95]([OH:101])=[O:96].[NH2:28][C:29]1[NH:30][C:31]([C:35]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]3[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=3)[C:4]=2[F:20])=[O:36])=[C:32]([Cl:34])[N:33]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Cl)c(C(=O)O)[nH]1
Agent: CC(C)(C)OC(=O)Nc1nc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(N)nc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.2 %

Procedure:
A mixture of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.041 g, 0.131 mmol), a 50:50 mixture of 2-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-chloro-1H-imidazole-5-carboxylic acid and 4-chloro-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-imidazole-5-carboxylic acid (0.047 g, 0.131 mmol), HATU (0.060 g, 0.157 mmol) and DIPEA (0.027 ml, 0.157 mmol) in DMF (1.5 mL) was stirred at RT overnight. The reaction mixture was extracted between EtOAc and water. The organic layer was washed with water and dried over sodium sulfate. The solvent was evaporated and the crude product was dissolved in dichloromethane (2 mL) and TFA (0.5 ml, 6.49 mmol) was added. The mixture was stirred at RT overnight. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.007 g, 6.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.56 (dd, 1H), 7.41-7.52 (m, 3H), 6.66 (s, 1H), 3.73 (s, 2H), 1.88 (br. s., 2H). ES MS: m/z 454 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[ClH:16].Cl[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH2:24]Cl)[CH:23]=1>>[Cl:16][C:19]1[CH:18]=[CH:23][C:22]([CH2:24][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:21][N:20]=1
Reactant: Cl
Reactant: ClCc1cncc(Cl)c1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(Cc3ccc(Cl)nc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=323.2 (M+H30), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-chloro-5-chloromethyl-pyridine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]([CH3:43])=[C:16]([N:28]([CH3:42])[CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[CH:17]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([CH:26]=O)=[CH:24][CH:25]=2)[CH:19]=1)=[O:13].[NH:44]1[CH2:49]COC[CH2:45]1.CO.C(O)(=O)C.[BH3-]C#N.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:13])[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([CH2:26][N:44]([CH3:49])[CH3:45])=[CH:24][CH:25]=2)[CH:17]=[C:16]([N:28]([CH3:42])[CH:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)[C:15]=1[CH3:43]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)nc3)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To a stirred solution of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-formylpyridin-3-yl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate (1 equiv.) and morpholine (5 equiv.) in methanol (5 mL for 0.3 mmol), acetic acid (1 equiv.) was added and reaction stirred at room temperature for 4 h. Then reducing agent NaBH3CN (1 equiv.) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and residue purified by column chromatography over silica gel affording desired tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-((dimethylamino)methyl)pyridin-3-yl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate. This compound was then dissolved in DCM (5 mL) and cooled to 0° C. TFA (2 mL) was added to it. The reaction mixture was stirred at room temperature for 1 h. On completion, reaction was concentrated to dryness. Residue was purified by solvent washings to afford the title compound (0.06 g, 40%). LCMS: 517.25 (M+1)+; HPLC: 99.07% (@ 254 nm) (Rt; 3.913; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.48 (s, 1H), 10.08 (bs, 1H), 8.97 (s, 1H), 8.57 (bs, 1H), 8.23 (d, 2H, J=7.6 Hz), 8.18 (s, 1H), 7.60 (d, 1H, J=8 Hz), 7.50 (s, 1H), 7.34 (s, 1H), 5.87 (s, 1H), 4.49 (d, 2H), 4.30 (s, 2H), 3.25 (d, 2H), 3.16 (s, 1H), 2.89 (m, 2H), 2.83 (s, 6H), 2.64 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.10 (s, 3H), 1.81 (bs, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].N1C=CC=CC=1.[F:16][CH:17]([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:23])[C:21]2[CH:20]=[CH:19][C:18]([CH:17]([F:16])[F:27])=[CH:26][CH:25]=2)=[C:3]([OH:9])[CH:4]=1
Reactant: O=C(Cl)c1ccc(C(F)F)cc1
Reactant: Nc1ccc(Br)cc1O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1O)c1ccc(C(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
4-(difluoromethyl)benzoic acid (0.7 g, 4 mmol) dissolved in DCM (20 ml), cooled to 0° C. and added oxalyl chloride (0.8 g, 6.1 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(difluoromethyl)benzoyl chloride quantitatively. 2-Amino-5-bromophenol (0.64 g, 3.4 mmol) dissolved in DCM (20 ml) and added Pyridine (0.32 ml, 4.1 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(difluoromethyl)benzoyl chloride (0.77 g, 4.1 mmol). After continuing stirring at rt for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (0.5 g) as a yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.27 (s, 1H), 9.62 (s, 1H), 8.07 (d, J 8.2, 2H), 7.71 (d, J 8.2, 2H), 7.61 (d, J 8.5, 1H), 7.12 (t, J 55.7, 1H), 7.07 (d, J 2.2, 1H), 7.03-6.94 (m, 1H).
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26](N)[CH2:27][CH2:28][CH2:29][CH3:30].S>C(O)C>[CH2:26]([NH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[S:25])[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCN
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Product: CCCCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 100 °C

Procedure:
A suspension of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2 g and pentylamine (3 cc) in absolute ethanol (30 cc) is saturated with hydrogen sulphide and then heated for 2 hours to a temperature in the region of 100° C. After being cooled, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The pasty residue is taken up with ethyl ether (50 cc) and distilled water (15 cc). The organic phase is separated, dried over potassium carbonate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual viscous yellow oil is purified by chromatography on a column (height: 35 cm; diameter: 2.6 cm) of silica gel (0.2-0.063 mm), eluting with ethyl acetate (300 cc) and collecting 25-cc fractions Fractions 3 to 9 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-Pentyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2.25 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+]>O1CCCC1>[CH2:1]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:19]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1cc2cc(OCCCNC(=O)NCc3ccccc3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1cc2cc(OCCCNC(=O)NCc3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To the solution of methyl 3-[5-(3-{[benzylamino]carbonylamino}propoxy)indolyl]propanoate (80 mg, 0.2 mmol), as prepared in the preceding step, in tetrahydrofuran (5 mL) and water (5 mL) was added sodium hydroxide (20 mg), and the reaction mixture was stirred at ambient temperature for 2 h. After evaporating the tetrahydrofuran, the aqueous solution was acidified (pH 5–6), the white solid formed was collected, washed with water and dried under high vacuum to give the title compound (65 mg, 82%). 1H-NMR (400 MHz, DMSO6) δ 7.21–7.37 (m, 7H), 7.02 (d, J=2.4 Hz, 1H), 6.78 (dd, J=8.8, 2.4 Hz, 1H), 6.36 (t, J=6.0 Hz, 1H), 6.30 (d, J=2.9 Hz, 1H), 6.06 (t, J=5.7 Hz, 1H), 4.34 (t, J=6.8 Hz, 2H), 4.20 (d, J=6.0 Hz, 2H), 3.96 (t, J 6.2 Hz, 2H), 3.19 (q, J=6.4 Hz, 2H), 2.71 (t, J=6.8 Hz, 2H), 1.83 (t, J=6.5 Hz, 2H). Mass spectrum (LCMS, ESI) Calcd. for C22H25N3O4 396.4 (M+H), found: 396.1.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]([C:44](=[O:48])[NH:45][CH2:46][CH3:47])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:7][O:8][C:9](=[O:37])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[C:13]([OH:36])[CH:12]=1)=[O:5])[CH3:2].C(N(CC)CC)C.Cl[C:57](Cl)([O:59]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[CH2:46]([NH:45][C:44]([C:6]([C:4](=[O:5])[NH:3][CH2:1][CH3:2])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:7][O:8][C:9](=[O:37])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]2[N:17]([C:18]([C:20]3[C:21]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:28][CH:27]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:19])[C:57](=[O:59])[O:36][C:13]=2[CH:12]=1)=[O:48])[CH3:47]
Reactant: CCNC(=O)C(COC(=O)Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(O)c1)(C(=O)NCC)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCNC(=O)C(COC(=O)Cc1ccc2c(c1)oc(=O)n2C(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1)(C(=O)NCC)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 213.3 %

Procedure:
The {3-Hydroxy-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetic acid 2,2-bisethylcarbamoyl-2-phenylethyl ester (195 mg) obtained in Example 3-2was dissolved in chloroform (5 mL), and to this solution was added triethylamine (72 mg). The solution was cooled to 0° C. and triphosgene (35 mg) was added thereto. After stirring for one hour, the reaction solution was washed with water, dried over sodium sulfate and purified by column chromatography on silica gel with hexane:ethyl acetate=1:1 to give the title compound (173 mg) (see Table 59).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:7]2[CH2:8][S:9][CH2:10][CH2:11][C:6]=2[C:5]2[C:12]([OH:25])=[CH:13][C:14]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])=[CH:15][C:4]=2[O:3]1.[ClH:27].[N:28]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:27].[CH3:26][C:2]1([CH3:1])[C:7]2[CH2:8][S:9][CH2:10][CH2:11][C:6]=2[C:5]2[C:12]([O:25][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:13][C:14]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])=[CH:15][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCSC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCSC1

Procedure:
The benzopyran of Example 21 is reacted with γ-piperidinobutyric acid hydrochloride and dicyclohexylcarbodiimide according to the method of Example 9 to yield the desired ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:8]=2)[CH2:3][CH2:2]1.C[O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:33][C:29]3[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=3)[C:26]([OH:35])=[O:25])[CH2:2][CH2:3]2)=[CH:8]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1ccc(CCn2cc(C3CCNCC3)c3ccccc32)nc1
Product: O=C(O)c1cccc(CN2CCC(c3cn(CCc4ccccn4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 3.4 g (11 mmol) of 3-piperidin-4-yl-1-(2-pyridin-2-yl-ethyl)-1H-indole and 2.7 g (11.5 mmol) of 3-bromomethyl-benzoic acid methyl ester. After standard work-up and recrystallisation with dichloromethane/methanol, 1.4 g (29% of yield) of the expected acid were obtained.